The Experts below are selected from a list of 246 Experts worldwide ranked by ideXlab platform
Wolfgang Baumgärtner - One of the best experts on this subject based on the ideXlab platform.
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insights into post translational processing of β galactosidase in an animal model resembling late infantile human GM1 Gangliosidosis
Journal of Cellular and Molecular Medicine, 2008Co-Authors: Robert Kreutzer, Mihaela Kreutzer, M J Pröpsting, Adrian C. Sewell, Tosso Leeb, Hassan Y. Naim, Wolfgang BaumgärtnerAbstract:GM1-Gangliosidosis is a lysosomal storage disorder caused by a deficiency of s-galactosidase activity. Human GM1-Gangliosidosis has been classified into three forms according to the age of clinical onset and specific biochemical parameters. In the present study, a canine model for type II late infantile human GM1-Gangliosidosis was investigated ‘in vitro’ in detail. For a better understanding of the molecular pathogenesis underlying GM1-Gangliosidosis the study focused on the analysis of the molecular events and subsequent intracellular protein trafficking of β-galactosidase. In the canine model the genetic defect results in exclusion or inclusion of exon 15 in the mRNA transcripts and to translation of two mutant precursor proteins. Intracellular localization, processing and enzymatic activity of these mutant proteins were investigated. The obtained results suggested that the β-galactosidase C-terminus encoded by exons 15 and 16 is necessary for correct C-terminal proteolytic processing and enzyme activity but does not affect the correct routing to the lysosomes. Both mutant protein precursors are enzymatically inactive, but are transported to the lysosomes clearly indicating that the amino acid sequences encoded by exons 15 and 16 are necessary for correct folding and association with protective protein/cathepsin A, whereas the routing to the lysosomes is not influenced. Thus, the investigated canine model is an appropriate animal model for the human late infantile form and represents a versatile system to test gene therapeutic approaches for human and canine GM1-Gangliosidosis.
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Insights into post‐translational processing of β‐galactosidase in an animal model resembling late infantile human GM1‐Gangliosidosis
Journal of cellular and molecular medicine, 2007Co-Authors: Robert Kreutzer, Mihaela Kreutzer, M J Pröpsting, Adrian C. Sewell, Tosso Leeb, Hassan Y. Naim, Wolfgang BaumgärtnerAbstract:GM1-Gangliosidosis is a lysosomal storage disorder caused by a deficiency of s-galactosidase activity. Human GM1-Gangliosidosis has been classified into three forms according to the age of clinical onset and specific biochemical parameters. In the present study, a canine model for type II late infantile human GM1-Gangliosidosis was investigated ‘in vitro’ in detail. For a better understanding of the molecular pathogenesis underlying GM1-Gangliosidosis the study focused on the analysis of the molecular events and subsequent intracellular protein trafficking of β-galactosidase. In the canine model the genetic defect results in exclusion or inclusion of exon 15 in the mRNA transcripts and to translation of two mutant precursor proteins. Intracellular localization, processing and enzymatic activity of these mutant proteins were investigated. The obtained results suggested that the β-galactosidase C-terminus encoded by exons 15 and 16 is necessary for correct C-terminal proteolytic processing and enzyme activity but does not affect the correct routing to the lysosomes. Both mutant protein precursors are enzymatically inactive, but are transported to the lysosomes clearly indicating that the amino acid sequences encoded by exons 15 and 16 are necessary for correct folding and association with protective protein/cathepsin A, whereas the routing to the lysosomes is not influenced. Thus, the investigated canine model is an appropriate animal model for the human late infantile form and represents a versatile system to test gene therapeutic approaches for human and canine GM1-Gangliosidosis.
Tadashi Miyatake - One of the best experts on this subject based on the ideXlab platform.
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Isolation and characterization of major urinary oligosaccharides excreted by a patient with type 3 GM1 Gangliosidosis.
Journal of biochemistry, 1991Co-Authors: Shoji Tsuji, Toshio Ariga, Susumu Ando, Yasukazu Tanaka, Kazuo Kon, Tomoyasu Yahagi, Keiko Ohta, Tadashi MiyatakeAbstract:Two major oligosaccharides were isolated from the urine of a patient with type 3 GM1 Gangliosidosis. From structural studies including compositional sugar analysis, fast-atom bombardment mass spectrometry, direct-inlet chemical ionization mass spectrometry, methylation analysis, chromium trioxide oxidation, and proton magnetic resonance spectroscopy, their structures were deduced to be as follows: [formula: see text] Both oligosaccharides have beta-linked galactose at the non-reducing ends. Oligosaccharide 1 is one of the most common urinary oligosaccharides found in type 1 and type 2 GM1 Gangliosidosis. Oligosaccharide 2, lacto-N-difucohexaose II, has not been described in the urine of GM1 Gangliosidosis patients. Excretion of oligosaccharide 1 in the type 3 patient was much less than that of a type 2 patient. Thin-layer chromatographic analysis revealed that the excretion of oligosaccharides with higher molecular weight than that of oligosaccharide 1 (octasaccharide) in the type 3 patient was much less than that of a type 2 patient, raising the possibility that the mutant beta-galactosidase of type 3 GM1 Gangliosidosis can still act to some extent on higher molecular weight oligosaccharides containing beta-linked galactose at the non-reducing end.
Robert Kreutzer - One of the best experts on this subject based on the ideXlab platform.
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insights into post translational processing of β galactosidase in an animal model resembling late infantile human GM1 Gangliosidosis
Journal of Cellular and Molecular Medicine, 2008Co-Authors: Robert Kreutzer, Mihaela Kreutzer, M J Pröpsting, Adrian C. Sewell, Tosso Leeb, Hassan Y. Naim, Wolfgang BaumgärtnerAbstract:GM1-Gangliosidosis is a lysosomal storage disorder caused by a deficiency of s-galactosidase activity. Human GM1-Gangliosidosis has been classified into three forms according to the age of clinical onset and specific biochemical parameters. In the present study, a canine model for type II late infantile human GM1-Gangliosidosis was investigated ‘in vitro’ in detail. For a better understanding of the molecular pathogenesis underlying GM1-Gangliosidosis the study focused on the analysis of the molecular events and subsequent intracellular protein trafficking of β-galactosidase. In the canine model the genetic defect results in exclusion or inclusion of exon 15 in the mRNA transcripts and to translation of two mutant precursor proteins. Intracellular localization, processing and enzymatic activity of these mutant proteins were investigated. The obtained results suggested that the β-galactosidase C-terminus encoded by exons 15 and 16 is necessary for correct C-terminal proteolytic processing and enzyme activity but does not affect the correct routing to the lysosomes. Both mutant protein precursors are enzymatically inactive, but are transported to the lysosomes clearly indicating that the amino acid sequences encoded by exons 15 and 16 are necessary for correct folding and association with protective protein/cathepsin A, whereas the routing to the lysosomes is not influenced. Thus, the investigated canine model is an appropriate animal model for the human late infantile form and represents a versatile system to test gene therapeutic approaches for human and canine GM1-Gangliosidosis.
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Insights into post‐translational processing of β‐galactosidase in an animal model resembling late infantile human GM1‐Gangliosidosis
Journal of cellular and molecular medicine, 2007Co-Authors: Robert Kreutzer, Mihaela Kreutzer, M J Pröpsting, Adrian C. Sewell, Tosso Leeb, Hassan Y. Naim, Wolfgang BaumgärtnerAbstract:GM1-Gangliosidosis is a lysosomal storage disorder caused by a deficiency of s-galactosidase activity. Human GM1-Gangliosidosis has been classified into three forms according to the age of clinical onset and specific biochemical parameters. In the present study, a canine model for type II late infantile human GM1-Gangliosidosis was investigated ‘in vitro’ in detail. For a better understanding of the molecular pathogenesis underlying GM1-Gangliosidosis the study focused on the analysis of the molecular events and subsequent intracellular protein trafficking of β-galactosidase. In the canine model the genetic defect results in exclusion or inclusion of exon 15 in the mRNA transcripts and to translation of two mutant precursor proteins. Intracellular localization, processing and enzymatic activity of these mutant proteins were investigated. The obtained results suggested that the β-galactosidase C-terminus encoded by exons 15 and 16 is necessary for correct C-terminal proteolytic processing and enzyme activity but does not affect the correct routing to the lysosomes. Both mutant protein precursors are enzymatically inactive, but are transported to the lysosomes clearly indicating that the amino acid sequences encoded by exons 15 and 16 are necessary for correct folding and association with protective protein/cathepsin A, whereas the routing to the lysosomes is not influenced. Thus, the investigated canine model is an appropriate animal model for the human late infantile form and represents a versatile system to test gene therapeutic approaches for human and canine GM1-Gangliosidosis.
Osamu Yamato - One of the best experts on this subject based on the ideXlab platform.
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Mutation analysis of GM1 Gangliosidosis in a Siamese cat from Japan in the 1960s
Journal of feline medicine and surgery, 2012Co-Authors: Mohammad Mejbah Uddin, Takeshi Tanimoto, Akira Yabuki, Takao Kotani, Mitsuru Kuwamura, Hye-sook Chang, Osamu YamatoAbstract:GM1 Gangliosidosis is a fatal, progressive neurodegenerative lysosomal storage disease caused by mutations of the β-galactosidase (GLB1) gene. In feline GM1 Gangliosidosis, a pathogenic mutation (c.1448G>C) of the feline GLB1 gene was identified in Siamese and Korat cats previously diagnosed with the disease in the USA and Italy, respectively. The present study demonstrated the same mutation in a Siamese cat that had been diagnosed with GM1 Gangliosidosis in Japan in the 1960s. The mutation was confirmed using DNA extracted from stored paraffin-embedded brain tissue by a direct sequencing method and a polymerase chain reaction–restriction fragment length polymorphism assay. This pathogenic mutation seems to have been distributed around the world.
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Serial MRI Features of Canine GM1 Gangliosidosis: A Possible Imaging Biomarker for Diagnosis and Progression of the Disease
TheScientificWorldJournal, 2012Co-Authors: Daisuke Hasegawa, Osamu Yamato, Akira Yabuki, Yuya Nakamoto, Tsuyoshi Ozawa, Kazuhito Itamoto, Takayuki Kuwabara, Michio Fujita, Kimimasa Takahashi, Shunta MizoguchiAbstract:GM1 Gangliosidosis is a fatal neurodegenerative lysosomal storage disease caused by an autosomal recessively inherited deficiency of β-galactosidase activity. Effective therapies need to be developed to treat the disease. In Shiba Inu dogs, one of the canine GM1 Gangliosidosis models, neurological signs of the disease, including ataxia, start at approximately 5 months of age and progress until the terminal stage at 12 to 15 months of age. In the present study, serial MR images were taken of an affected dog from a model colony of GM1 Gangliosidosis and 4 sporadic clinical cases demonstrating the same mutation in order to characterize the MRI features of this canine GM1 Gangliosidosis. By 2 months of age at the latest and persisting until the terminal stage of the disease, the MR findings consistently displayed diffuse hyperintensity in the white matter of the entire cerebrum on T2-weighted images. In addition, brain atrophy manifested at 9 months of age and progressed thereafter. Although a definitive diagnosis depends on biochemical and genetic analyses, these MR characteristics could serve as a diagnostic marker in suspect animals with or without neurological signs. Furthermore, serial changes in MR images could be used as a biomarker to noninvasively monitor the efficacy of newly developed therapeutic strategies.
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Pathological Features of Salivary Gland Cysts in a Shiba Dog with GM1 Gangliosidosis: A Possible Misdiagnosis as Malignancy
The Journal of veterinary medical science, 2011Co-Authors: Mohammad Mahbubur Rahman, Akira Yabuki, Yuya Nakamoto, Tsuyoshi Ozawa, Hiroaki Kawaguchi, Noriaki Miyoshi, Osamu YamatoAbstract:Salivary gland cysts are often concurrent with GM1 Gangliosidosis in Shiba dogs. Although the etiology is unknown, these cysts may be misdiagnosed as malignant due to the accumulation of foamy cells. The present study investigated the cytological, histopathological, immunohistochemical and electron microscopic characteristics of salivary gland cysts in a Shiba dog affected with GM1 Gangliosidosis. The salivary gland masses were surgically enucleated and examined clinicopathologically and pathologically in a 7-month-old Shiba dog with GM1 Gangliosidosis. Many large cells with rich cytoplasm including vacuoles of various sizes, i.e., foamy cells, were observed in stamp smears from the cut-surface of the masses and histopathologically in major parts of the cyst wall. Some of these foamy cells presented features similar to a spider-web appearance. The foamy cells were confirmed to have originated from macrophages based on marked immunohistochemical expression of vimentin, HLA-DR, lysozyme and Iba1. An ultrastructural study demonstrated electron-dense vesicular structures in the vacuolated cells. Therefore, the masses were diagnosed pathologically as benign salivary gland cysts with accumulation of foamy cells. In conclusion, the histopathological features of the salivary gland cysts in this Shiba dog were similar to those of lipoma and/or liposarcoma. In such cases, immunohistochemical and ultrastructural examinations were useful in the differential diagnosis. Practitioners, clinical pathologists and pathologists should take GM1 Gangliosidosis into consideration when they encounter salivary gland cysts in Shiba dogs.
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Morphological Analysis of Corneal Opacity in Shiba Dog with GM1 Gangliosidosis
Journal of Veterinary Medical Science, 2008Co-Authors: Aya Nagayasu, Taito Nakamura, Yoshinao Hosaka, Prasarn Tangkawattana, Osamu Yamato, Keiko Tsuzuki, Hiromi Ueda, Kazushige TakehanaAbstract:GM1 Gangliosidosis is one of the inherited metabolic lysosomal storage disorders characterized by neurological symptoms caused by β-galactosidase deficiency and consequent accumulation of GM1 ganglioside in neuronal cells. Shiba dogs affected with GM1 Gangliosidosis have been found to suffer from corneal opacity. In our morphological analysis, keratocyte enlargement was induced by abnormal intracellular accumulation of neutral carbohydrates, resulting in the loss of normal arrangement of collagen fibrils in the opaque cornea was found to be associated with the disorder. We therefore conclude that corneal opacity in this Shiba dog with GM1 Gangliosidosis may be caused by neutral carbohydrate accumulation in lysosomes, swelling and dysfunction of keratocytes, and subsequent irregular arrangement of collagen fibrils in the corneal proper substance.
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cerebrospinal fluid biomarkers showing neurodegeneration in dogs with GM1 Gangliosidosis possible use for assessment of a therapeutic regimen
Brain Research, 2007Co-Authors: Hiroyuki Satoh, Madoka Yonemura, Toyofumi Yamauchi, Tomoya Asano, Hiromitsu Orima, Osamu Yamato, Daisuke Hasegawa, Toshiro Arai, Masahiro Yamasaki, Yoshimitsu MaedeAbstract:The present study investigated cerebrospinal fluid (CSF) biomarkers for estimating degeneration of the central nervous system (CNS) in experimental dogs with GM1 Gangliosidosis and preliminarily evaluated the efficacy of long-term glucocorticoid therapy for GM1 Gangliosidosis using the biomarkers identified here. GM1 Gangliosidosis, a lysosomal storage disease that affects the brain and multiple systemic organs, is due to an autosomal recessively inherited deficiency of acid β-galactosidase activity. Pathogenesis of GM1 Gangliosidosis may include neuronal apoptosis and abnormal axoplasmic transport and inflammatory response, which are perhaps consequent to massive neuronal storage of GM1 ganglioside. In the present study, we assessed some possible CSF biomarkers, such as GM1 ganglioside, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), neuron-specific enolase (NSE) and myelin basic protein (MBP). Periodic studies demonstrated that GM1 ganglioside concentration, activities of AST and LDH, and concentrations of NSE and MBP in CSF were significantly higher in dogs with GM1 Gangliosidosis than those in control dogs, and their changes were well related with the months of age and clinical course. In conclusion, GM1 ganglioside, AST, LDH, NSE and MBP could be utilized as CSF biomarkers showing CNS degeneration in dogs with GM1 Gangliosidosis to evaluate the efficacy of novel therapies proposed for this disease. In addition, we preliminarily treated an affected dog with long-term oral administration of prednisolone and evaluated the efficacy of this therapeutic trial using CSF biomarkers determined in the present study. However, this treatment did not change either the clinical course or the CSF biomarkers of the affected dog, suggesting that glucocorticoid therapy would not be effective for treating GM1 Gangliosidosis.
Shoji Tsuji - One of the best experts on this subject based on the ideXlab platform.
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Isolation and characterization of major urinary oligosaccharides excreted by a patient with type 3 GM1 Gangliosidosis.
Journal of biochemistry, 1991Co-Authors: Shoji Tsuji, Toshio Ariga, Susumu Ando, Yasukazu Tanaka, Kazuo Kon, Tomoyasu Yahagi, Keiko Ohta, Tadashi MiyatakeAbstract:Two major oligosaccharides were isolated from the urine of a patient with type 3 GM1 Gangliosidosis. From structural studies including compositional sugar analysis, fast-atom bombardment mass spectrometry, direct-inlet chemical ionization mass spectrometry, methylation analysis, chromium trioxide oxidation, and proton magnetic resonance spectroscopy, their structures were deduced to be as follows: [formula: see text] Both oligosaccharides have beta-linked galactose at the non-reducing ends. Oligosaccharide 1 is one of the most common urinary oligosaccharides found in type 1 and type 2 GM1 Gangliosidosis. Oligosaccharide 2, lacto-N-difucohexaose II, has not been described in the urine of GM1 Gangliosidosis patients. Excretion of oligosaccharide 1 in the type 3 patient was much less than that of a type 2 patient. Thin-layer chromatographic analysis revealed that the excretion of oligosaccharides with higher molecular weight than that of oligosaccharide 1 (octasaccharide) in the type 3 patient was much less than that of a type 2 patient, raising the possibility that the mutant beta-galactosidase of type 3 GM1 Gangliosidosis can still act to some extent on higher molecular weight oligosaccharides containing beta-linked galactose at the non-reducing end.